chr22-46364168-C-T

Position:

chr22-46364168-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001378328.1(CELSR1):c.8863G>A(p.Ala2955Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,612,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CELSR1
NM_001378328.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Variant links:

Genes affected

CELSR1 (HGNC:1850): (cadherin EGF LAG seven-pass G-type receptor 1) The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consists of nonclassic-type cadherins; a subpopulation that does not interact with catenins. The flamingo cadherins are located at the plasma membrane and have nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic unique to this subfamily. It is postulated that these proteins are receptors involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions. This particular member is a developmentally regulated, neural-specific gene which plays an unspecified role in early embryogenesis. [provided by RefSeq, Jul 2008]

CELSR1 links:

CELSR1 (HGNC:):

CELSR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03340456).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR1	NM_001378328.1 linkuse as main transcript	c.8863G>A	p.Ala2955Thr	missense_variant	34/35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CELSR1	ENST00000674500.2 linkuse as main transcript	c.8863G>A	p.Ala2955Thr	missense_variant	34/35		NM_001378328.1	ENSP00000501367.2	A0A6I8PRU0
CELSR1	ENST00000262738.9 linkuse as main transcript	c.8863G>A	p.Ala2955Thr	missense_variant	34/35	1		ENSP00000262738.3	Q9NYQ6-1
CELSR1	ENST00000473624.2 linkuse as main transcript	c.616G>A	p.Ala206Thr	missense_variant	5/5	1		ENSP00000501353.1	A0A6I8PL36
CELSR1	ENST00000674159.1 linkuse as main transcript	n.2306G>A		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000727

AC:

AN:

247706

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000936

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1459818

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

726220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00456

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.8863G>A (p.A2955T) alteration is located in exon 34 (coding exon 34) of the CELSR1 gene. This alteration results from a G to A substitution at nucleotide position 8863, causing the alanine (A) at amino acid position 2955 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.99

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Uncertain

0.014

Sift4G

Uncertain

0.017

Polyphen

0.93

Vest4

0.16

MutPred

0.083

Gain of phosphorylation at A2955 (P = 0.0341);

MVP

0.67

MPC

0.27

ClinPred

0.15

GERP RS

3.8

Varity_R

0.13

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over